Epidemiological and Genetic Investigations of Blood-Based Biomarkers for Alzheimer's Disease in the Multiethnic, Washington Heights, Inwood, Columbia Aging Project (WHICAP)

摘要。脑脊液和PET分子标记物Aβ和磷酸化tau蛋白的分析 结合MRI评估整体和区域神经退行性变导致了“A/T/N”的发展， 阿尔茨海默病（AD）的分类方案，旨在增加临床诊断的精确度， 目的、治疗试验和监管机构。对于观察性流行病学研究， 由于回旋加速器的费用和有限的使用， 分子成像所必需的以及在大型研究中获取CSF的困难。此外，很明显， 生物标志物值与临床诊断的关系也可能因年龄、性别和种族/民族而异，并且很少有 研究包括代表美国人群的不同队列。新时代的到来- 已建立的基于血液的生物标志物（Aβ40、Aβ42、p-tau 217、神经丝轻链或NFL）与 脑MRI提供了研究“A/T/N生物标志物谱”在基于社区的， 观察性研究，并创建可用于识别遗传易感性的内在表型。 华盛顿高地，因伍德哥伦比亚老龄化项目（WHICAP）的研究是少数几个队列之一， 可以使用新建立的基于血液的生物标志物和成熟的AD神经影像学生物标志物 研究基于血液的“A/T/N生物标志物谱”，包括人种/种族组和年龄和性别。淀粉样 （血浆Aβ40和Aβ42）、Tau（血浆总tau和p-tau 217）和神经变性（血浆神经丝 光[NfL]和MRI（脑体积和皮质厚度）将在纵向、多种族 基于社区的老年人队列（24%非西班牙裔白色白人，28%非洲裔美国人，48%加勒比海西班牙裔）。 该队列已被遗传表征，并已储存DNA、血清和血浆。的影响 脑血管疾病“V”和心理社会因素也将作为潜在的调节剂进行研究， “A/T/N生物标志物图谱”。我们将使用非裔美国人、加勒比海西班牙裔美国人和美国人的公开遗传数据， 和非西班牙裔白色参与者，包括WHICAP队列，以创建种族特异性多基因风险 评分（ePRS）。这将允许鉴定与潜在的内表型相关的变异， “A/T/N生物标志物谱”，并增强ePRS与AD临床诊断的关联。 我们将保持对WHICAP队列的纵向随访，仅增加参与者以解释自然减员， 采集全血用于血浆和血清，确定心理社会和生物医学风险和保护因素 在四年的时间里，至少对参与者进行两次结构性MRI测量。的总目标 该项目的目的是：1）研究血液生物标志物和MRI测量中“A/T/N生物标志物”的变异性 2）研究血液生物标志物， 内表型在遗传分析中的早期检测和诊断AD; 3）研究如何 脑血管疾病和心理社会因素调节血液和MRI生物标志物的使用。

ABSTRACT. The analysis of cerebrospinal fluid (CSF) and molecular PET biomarkers of Aβ and phospho-tau combined with MRI assessment of global and regional neurodegeneration led to the development of the “A/T/N” classification scheme for Alzheimer's disease (AD) that was intended to add precision to the diagnosis for clinical purposes, therapeutic trials and regulatory agencies. For observational epidemiological research the widespread use of these types of biomarkers is not possible because of the expense and limited access to cyclotrons necessary for molecular imaging and the difficulty in obtaining CSF in large studies. Further, it is clear that the relationship of biomarker values to clinical diagnoses can also differ by age, sex and race/ethnic group, and few studies have included diverse cohorts, representative of the population in the US. The advent of newly- established, blood-based biomarkers (Aβ40, Aβ42, p-tau217, neurofilament light chain or NFL) combined with brain MRI provides an opportunity to investigate the application of “A/T/N biomarker profile” in community-based, observational study, and create endophenotypes that can be used to identify genetic susceptibility. The Washington Heights, Inwood Columbia Aging Project (WHICAP) study is one of the few cohorts where the newly established blood-based biomarkers and well-established neuroimaging biomarkers for AD can be used to investigate a blood-based “A/T/N biomarker profile” across race/ethnic groups and by age and sex. Amyloid (plasma Aβ40 and Aβ42), Tau (plasma total tau and p-tau217), and Neurodegeneration (plasma neurofilament light [NfL], and MRI (brain volumes and cortical thickness) will be assessed in a longitudinal, multi-ethnic community-based elderly cohort (24% white non-Hispanic, 28% African American, 48% Caribbean Hispanic). The cohort has been genetically characterized, and has stored DNA, sera, and plasma. The effects of cerebrovascular disease “V” and psychosocial factors will also be investigated as potential modulators of the “A/T/N biomarker profile”. We will use publicly available genetic data in African American, Caribbean Hispanic and non-Hispanic white participants that included the WHICAP cohort to create ethnic-specific polygenic risk scores (ePRS). This will allow the identification of variants associated with the endophenotypes underlying the “A/T/N biomarker profile” and augment the ePRS association with the clinical diagnoses of AD. We will maintain longitudinal follow-up of the WHICAP cohort, adding participants only to account for attrition, collecting whole blood for plasma and sera, ascertaining psychosocial and biomedical risk and protective factors and obtaining structural MRI measures at least twice in participants over a four-year period. The overall goals of this project are to: 1) investigate variability in blood-based biomarkers and MRI measures in the “A/T/N biomarker profile” as it applies to clinical diagnoses in a multi-ethnic cohort; 2) investigate blood-based biomarkers as endophenotypes in genetic analyses for earlier detection and diagnosis of AD; 3) investigate how cerebrovascular disease and psychosocial factors modulate the use of blood-based and MRI biomarkers.